A model system for studying leukemia cell differentiation in vitro has been constructed. The HL-60 cell line, established from human promyelocytic leukemia, was used to obtain a variant cell line, 1F10, which, contrary to the original HL60 cell line, needs two inducers to differentiate into monocyte/macrophage-like cells. The two inducers, when used separately, allow us to define discrete complementary steps in the differentiation pathway. The goal of this proposal is to use this new model system for studying the molecular genetics of leukemia cell differentiation. For this purpose, we will identify and isolate the genes that are specifically activated at these discrete steps of the differentiation pathway by applying cDNA subtraction procedures and cloning. As a consequence of this cloning, we will also try to isolate genes whose products can activate or repress progression of cells into the differentiation pathway. The model that we propose here, is a direct approach to investigate the genetic aspects of leukemia cell differentiation, thus furthering our understanding of the leukemogenesis process in human.